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- EMDB-23544: Human phosphofructokinase-1 liver type bound to activator NA-11 -

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Basic information

Entry
Database: EMDB / ID: EMD-23544
TitleHuman phosphofructokinase-1 liver type bound to activator NA-11
Map dataHuman phosphofructokinase-1 liver type bound to activator NA-11
Sample
  • Complex: Human phosphofructokinase-1 liver type bound to activator NA-11
    • Protein or peptide: ATP-dependent 6-phosphofructokinase, liver type
  • Ligand: N-{(11S)-2-[2-(5-hydroxypent-1-yn-1-yl)phenyl]-4H,10H-pyrazolo[5,1-c][1,4]benzoxazepin-7-yl}acetamide
  • Ligand: 1,6-di-O-phosphono-beta-D-fructofuranose
  • Ligand: 6-O-phosphono-beta-D-fructofuranose
  • Ligand: ADENOSINE-5'-DIPHOSPHATE
Function / homology
Function and homology information


fructose binding / 6-phosphofructokinase complex / 6-phosphofructokinase / fructose-6-phosphate binding / 6-phosphofructokinase activity / fructose 1,6-bisphosphate metabolic process / fructose 6-phosphate metabolic process / monosaccharide binding / canonical glycolysis / Glycolysis ...fructose binding / 6-phosphofructokinase complex / 6-phosphofructokinase / fructose-6-phosphate binding / 6-phosphofructokinase activity / fructose 1,6-bisphosphate metabolic process / fructose 6-phosphate metabolic process / monosaccharide binding / canonical glycolysis / Glycolysis / AMP binding / negative regulation of insulin secretion / response to glucose / glycolytic process / kinase binding / secretory granule lumen / ficolin-1-rich granule lumen / Neutrophil degranulation / extracellular exosome / extracellular region / ATP binding / membrane / identical protein binding / metal ion binding / cytosol
Similarity search - Function
ATP-dependent 6-phosphofructokinase, vertebrate-type / ATP-dependent 6-phosphofructokinase, eukaryotic-type / Phosphofructokinase, conserved site / Phosphofructokinase signature. / Phosphofructokinase domain / ATP-dependent 6-phosphofructokinase / Phosphofructokinase superfamily / Phosphofructokinase
Similarity search - Domain/homology
ATP-dependent 6-phosphofructokinase, liver type
Similarity search - Component
Biological speciesHomo sapiens (human)
Methodsingle particle reconstruction / cryo EM / Resolution: 2.9 Å
AuthorsLynch EM / Kollman JM / Webb B
Funding support United States, 1 items
OrganizationGrant numberCountry
National Institutes of Health/National Institute of General Medical Sciences (NIH/NIGMS)R01GM118396 United States
CitationJournal: Cell / Year: 2021
Title: Selective activation of PFKL suppresses the phagocytic oxidative burst.
Authors: Neri Amara / Madison P Cooper / Maria A Voronkova / Bradley A Webb / Eric M Lynch / Justin M Kollman / Taylur Ma / Kebing Yu / Zijuan Lai / Dewakar Sangaraju / Nobuhiko Kayagaki / Kim Newton ...Authors: Neri Amara / Madison P Cooper / Maria A Voronkova / Bradley A Webb / Eric M Lynch / Justin M Kollman / Taylur Ma / Kebing Yu / Zijuan Lai / Dewakar Sangaraju / Nobuhiko Kayagaki / Kim Newton / Matthew Bogyo / Steven T Staben / Vishva M Dixit /
Abstract: In neutrophils, nicotinamide adenine dinucleotide phosphate (NADPH) generated via the pentose phosphate pathway fuels NADPH oxidase NOX2 to produce reactive oxygen species for killing invading ...In neutrophils, nicotinamide adenine dinucleotide phosphate (NADPH) generated via the pentose phosphate pathway fuels NADPH oxidase NOX2 to produce reactive oxygen species for killing invading pathogens. However, excessive NOX2 activity can exacerbate inflammation, as in acute respiratory distress syndrome (ARDS). Here, we use two unbiased chemical proteomic strategies to show that small-molecule LDC7559, or a more potent designed analog NA-11, inhibits the NOX2-dependent oxidative burst in neutrophils by activating the glycolytic enzyme phosphofructokinase-1 liver type (PFKL) and dampening flux through the pentose phosphate pathway. Accordingly, neutrophils treated with NA-11 had reduced NOX2-dependent outputs, including neutrophil cell death (NETosis) and tissue damage. A high-resolution structure of PFKL confirmed binding of NA-11 to the AMP/ADP allosteric activation site and explained why NA-11 failed to agonize phosphofructokinase-1 platelet type (PFKP) or muscle type (PFKM). Thus, NA-11 represents a tool for selective activation of PFKL, the main phosphofructokinase-1 isoform expressed in immune cells.
History
DepositionFeb 27, 2021-
Header (metadata) releaseJan 26, 2022-
Map releaseJan 26, 2022-
UpdateJan 26, 2022-
Current statusJan 26, 2022Processing site: RCSB / Status: Released

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Structure visualization

Movie
  • Surface view with section colored by density value
  • Surface level: 1.1
  • Imaged by UCSF Chimera
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  • Surface view colored by radius
  • Surface level: 1.1
  • Imaged by UCSF Chimera
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  • Surface view with fitted model
  • Atomic models: PDB-7lw1
  • Surface level: 1.1
  • Imaged by UCSF Chimera
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  • Simplified surface model + fitted atomic model
  • Atomic modelsPDB-7lw1
  • Imaged by Jmol
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Movie viewer
Structure viewerEM map:
SurfViewMolmilJmol/JSmol
Supplemental images

emd_23544.png

Downloads & links

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Map

FileDownload / File: emd_23544.map.gz / Format: CCP4 / Size: 103 MB / Type: IMAGE STORED AS FLOATING POINT NUMBER (4 BYTES)
AnnotationHuman phosphofructokinase-1 liver type bound to activator NA-11
Voxel sizeX=Y=Z: 1.05 Å
Density
Contour LevelBy AUTHOR: 1.1 / Movie #1: 1.1
Minimum - Maximum-9.377575 - 14.239031
Average (Standard dev.)5.3285815e-13 (±0.33414817)
SymmetrySpace group: 1
Details

EMDB XML:

Map geometry
Axis orderZYX
Origin000
Dimensions300300300
Spacing300300300
CellA=B=C: 315.0 Å
α=β=γ: 90.0 °

CCP4 map header:

modeImage stored as Reals
Å/pix. X/Y/Z1.051.051.05
M x/y/z300300300
origin x/y/z0.0000.0000.000
length x/y/z315.000315.000315.000
α/β/γ90.00090.00090.000
start NX/NY/NZ000
NX/NY/NZ300300300
MAP C/R/S321
start NC/NR/NS000
NC/NR/NS300300300
D min/max/mean-9.37814.2390.000

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Supplemental data

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Sample components

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Entire : Human phosphofructokinase-1 liver type bound to activator NA-11

EntireName: Human phosphofructokinase-1 liver type bound to activator NA-11
Components
  • Complex: Human phosphofructokinase-1 liver type bound to activator NA-11
    • Protein or peptide: ATP-dependent 6-phosphofructokinase, liver type
  • Ligand: N-{(11S)-2-[2-(5-hydroxypent-1-yn-1-yl)phenyl]-4H,10H-pyrazolo[5,1-c][1,4]benzoxazepin-7-yl}acetamide
  • Ligand: 1,6-di-O-phosphono-beta-D-fructofuranose
  • Ligand: 6-O-phosphono-beta-D-fructofuranose
  • Ligand: ADENOSINE-5'-DIPHOSPHATE

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Supramolecule #1: Human phosphofructokinase-1 liver type bound to activator NA-11

SupramoleculeName: Human phosphofructokinase-1 liver type bound to activator NA-11
type: complex / ID: 1 / Parent: 0 / Macromolecule list: #1
Source (natural)Organism: Homo sapiens (human)
Recombinant expressionOrganism: unidentified baculovirus

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Macromolecule #1: ATP-dependent 6-phosphofructokinase, liver type

MacromoleculeName: ATP-dependent 6-phosphofructokinase, liver type / type: protein_or_peptide / ID: 1 / Number of copies: 4 / Enantiomer: LEVO / EC number: 6-phosphofructokinase
Source (natural)Organism: Homo sapiens (human)
Molecular weightTheoretical: 85.120375 KDa
Recombinant expressionOrganism: unidentified baculovirus
SequenceString: MAAVDLEKLR ASGAGKAIGV LTSGGDAQGM NAAVRAVTRM GIYVGAKVFL IYEGYEGLVE GGENIKQANW LSVSNIIQLG GTIIGSARC KAFTTREGRR AAAYNLVQHG ITNLCVIGGD GSLTGANIFR SEWGSLLEEL VAEGKISETT ARTYSHLNIA G LVGSIDND ...String:
MAAVDLEKLR ASGAGKAIGV LTSGGDAQGM NAAVRAVTRM GIYVGAKVFL IYEGYEGLVE GGENIKQANW LSVSNIIQLG GTIIGSARC KAFTTREGRR AAAYNLVQHG ITNLCVIGGD GSLTGANIFR SEWGSLLEEL VAEGKISETT ARTYSHLNIA G LVGSIDND FCGTDMTIGT DSALHRIMEV IDAITTTAQS HQRTFVLEVM GRHCGYLALV SALASGADWL FIPEAPPEDG WE NFMCERL GETRSRGSRL NIIIIAEGAI DRNGKPISSS YVKDLVVQRL GFDTRVTVLG HVQRGGTPSA FDRILSSKMG MEA VMALLE ATPDTPACVV TLSGNQSVRL PLMECVQMTK EVQKAMDDKR FDEATQLRGG SFENNWNIYK LLAHQKPPKE KSNF SLAIL NVGAPAAGMN AAVRSAVRTG ISHGHTVYVV HDGFEGLAKG QVQEVGWHDV AGWLGRGGSM LGTKRTLPKG QLESI VENI RIYGIHALLV VGGFEAYEGV LQLVEARGRY EELCIVMCVI PATISNNVPG TDFSLGSDTA VNAAMESCDR IKQSAS GTK RRVFIVETMG GYCGYLATVT GIAVGADAAY VFEDPFNIHD LKVNVEHMTE KMKTDIQRGL VLRNEKCHDY YTTEFLY NL YSSEGKGVFD CRTNVLGHLQ QGGAPTPFDR NYGTKLGVKA MLWLSEKLRE VYRKGRVFAN APDSACVIGL KKKAVAFS P VTELKKDTDF EHRMPREQWW LSLRLMLKML AQYRISMAAY VSGELEHVTR RTLSMDKGF

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Macromolecule #2: N-{(11S)-2-[2-(5-hydroxypent-1-yn-1-yl)phenyl]-4H,10H-pyrazolo[5,...

MacromoleculeName: N-{(11S)-2-[2-(5-hydroxypent-1-yn-1-yl)phenyl]-4H,10H-pyrazolo[5,1-c][1,4]benzoxazepin-7-yl}acetamide
type: ligand / ID: 2 / Number of copies: 4 / Formula: YG1
Molecular weightTheoretical: 401.458 Da
Chemical component information

ChemComp-YG1:
N-{(11S)-2-[2-(5-hydroxypent-1-yn-1-yl)phenyl]-4H,10H-pyrazolo[5,1-c][1,4]benzoxazepin-7-yl}acetamide

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Macromolecule #3: 1,6-di-O-phosphono-beta-D-fructofuranose

MacromoleculeName: 1,6-di-O-phosphono-beta-D-fructofuranose / type: ligand / ID: 3 / Number of copies: 4 / Formula: FBP
Molecular weightTheoretical: 340.116 Da
Chemical component information

ChemComp-FBP:
1,6-di-O-phosphono-beta-D-fructofuranose / Fructose 1,6-bisphosphate

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Macromolecule #4: 6-O-phosphono-beta-D-fructofuranose

MacromoleculeName: 6-O-phosphono-beta-D-fructofuranose / type: ligand / ID: 4 / Number of copies: 4 / Formula: F6P
Molecular weightTheoretical: 260.136 Da
Chemical component information

ChemComp-F6P:
6-O-phosphono-beta-D-fructofuranose / Fructose 6-phosphate

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Macromolecule #5: ADENOSINE-5'-DIPHOSPHATE

MacromoleculeName: ADENOSINE-5'-DIPHOSPHATE / type: ligand / ID: 5 / Number of copies: 4 / Formula: ADP
Molecular weightTheoretical: 427.201 Da
Chemical component information

ChemComp-ADP:
ADENOSINE-5'-DIPHOSPHATE / ADP, energy-carrying molecule*YM / Adenosine diphosphate

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Experimental details

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Structure determination

Methodcryo EM
Processingsingle particle reconstruction
Aggregation stateparticle

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Sample preparation

BufferpH: 7.5
GridModel: C-flat-2/2 / Material: COPPER / Mesh: 400 / Pretreatment - Type: GLOW DISCHARGE
VitrificationCryogen name: ETHANE / Chamber humidity: 100 % / Instrument: FEI VITROBOT MARK IV

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Electron microscopy

MicroscopeFEI TITAN KRIOS
Electron beamAcceleration voltage: 300 kV / Electron source: FIELD EMISSION GUN
Electron opticsIllumination mode: FLOOD BEAM / Imaging mode: BRIGHT FIELDBright-field microscopy / Cs: 2.7 mm / Nominal defocus max: 2.8000000000000003 µm / Nominal defocus min: 0.7000000000000001 µm / Nominal magnification: 130000
Sample stageSpecimen holder model: FEI TITAN KRIOS AUTOGRID HOLDER / Cooling holder cryogen: NITROGEN
Image recordingFilm or detector model: GATAN K2 SUMMIT (4k x 4k) / Detector mode: SUPER-RESOLUTION / Digitization - Dimensions - Width: 3710 pixel / Digitization - Dimensions - Height: 3838 pixel / Digitization - Frames/image: 1-50 / Number grids imaged: 1 / Number real images: 2529 / Average exposure time: 10.0 sec. / Average electron dose: 90.0 e/Å2
Experimental equipment
Model: Titan Krios / Image courtesy: FEI Company

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Image processing

Particle selectionNumber selected: 3000000
CTF correctionSoftware - Name: CTFFIND (ver. 4)
Initial angle assignmentType: MAXIMUM LIKELIHOOD / Software - Name: RELION (ver. 3.1)
Final 3D classificationNumber classes: 4 / Software - Name: RELION (ver. 3.1)
Final angle assignmentType: MAXIMUM LIKELIHOOD / Software - Name: RELION (ver. 3.1)
Final reconstructionApplied symmetry - Point group: D2 (2x2 fold dihedral) / Resolution.type: BY AUTHOR / Resolution: 2.9 Å / Resolution method: FSC 0.5 CUT-OFF / Software - Name: RELION (ver. 3.1) / Number images used: 63296

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